Absorbable α-cyanoacrylate compositions

ABSTRACT

A monomer composition comprising at least one polymerizable alkyl ester α-cyanoacrylate monomer. Specifically, the α-cyanoacrylate monomer is an alkyl ester α-cyanoacrylate monomer of the general formula having a spacer R1: 
                         
n is from 2 to 12; R3 and R4 are each an alkyl group or a hydrogen, and at least one of R3 or R4 is an alkyl group (e.g. linear or branched, or cyclic) having from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13 carbon atoms; R2 is an alkyl group (e.g. linear or branched, or cyclic) having from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13 carbon atoms; and the combined number of carbon atoms (N) in the spacer R1 is at least n+1.

This application is a Divisional of U.S. application Ser. No. 11/088587filed on 24 Mar. 2005, which issued into U.S. Pat. No. 7,238,828. Thecomplete disclosure of the aforementioned related U.S. patent is herebyincorporated herein by reference for all purposes.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a new class of α-cyanoacrylate monomers whichare useful as adhesives or sealants, and more particularly to compoundswhich are alkyl ester α-cyanoacrylate monomers. This invention furtherrelates to the use of such alkyl ester α-cyanoacrylates monomers inα-cyanoacrylate compositions that are useful as tissueadhesives/sealants in surgical, medical and industrial applications, andto the production thereof.

2. State of the Art

Monomer and polymer adhesives/sealants are used in both industrial(including household) and medical/surgical applications. Included amongthese adhesives or sealants are the α-cyanoacrylates monomers andpolymers resulting therefrom. Since the discovery of theadhesive/sealant properties of such monomers and polymers, they havefound wide use due to the speed with which they cure, the strength ofthe resulting bond formed, and their relative ease of use. Thesecharacteristics have made α-cyanoacrylate compositions the primarychoice for numerous adhesive applications such as bonding plastics,rubbers, glass, metals, wood, and, more recently, medical, biological orliving tissues.

Medical and surgical applications of α-cyanoacrylate compositionsinclude their use as alternates or adjuncts to surgical sutures, meshesand staples or other medical devices in wound closure, as well as forcovering and protecting surface wounds such as lacerations, abrasions,burns, stomatitis, sores, and other surface wounds. When anα-cyanoacrylate composition is applied, it is usually applied in itsmonomeric form, and the resultant polymerization gives rise to thedesired adhesive bond or sealant strength.

For example, polymerizable α-cyanoacrylate monomers and compositionscomprising such monomers are disclosed in U.S. Pat. No. 5,328,687 toLeung et al. Suitable methods for applying such compositions tosubstrates, and particularly in medical applications, are described in,for example, U.S. Pat. Nos. 6,620,846 B1, 6,512,023B1, and 3,995,641,the contents each of which is incorporated by reference herein in itsentirety.

U.S. Pat. No. 5,928,611 to Leung broadly discloses α-cyanoacrylatemonomers having a large number of possible substituent groups. Thedisclosure focuses on α-cyanoacrylate monomers, with alternativerepresentation of ester cyanoacrylate monomers having an organic radicalsubstituent. However, the disclosure does not specify particularproperties, such as absorbability, possessed by polymers formed withparticular cyanoacrylate monomers.

U.S. Pat. No. 3,995,641 to Kronenthal et al. discloses carbalkoxyalkylα-cyanoacrylate monomers that form absorbable polymer adhesives inmammalian tissue. Under some circumstances, absorbable polymeradhesives/sealants have benefits over non-absorbable polymeradhesives/sealants, particularly for some medical applications. However,some α-cyanoacrylate monomers have particularly slow reaction kineticswhich reduce their practical value as surgical adhesives/sealants.

Therefore, there is still a need for α-cyanoacrylate compositions thatexhibit a rapid cure rate sufficient for medical applications andproduce an absorbable polymer adhesive/sealant. It is also desirable tohave a monomer based internal adhesive or sealant composition that iscapable of polymerizing in vivo to form an internal adhesive or sealant,in order to provide an opportunity for manipulation and re-alignment.Specifically, it is desirable that the adhesive or sealant compositionfill internal cavities and voids, penetrating and conforming to theinterstices and pores of the tissue, prior to curing or setting.

Additionally, it is desirable to have a monomer based internal adhesiveor sealant composition that polymerizes in vivo, where the monomer, thecomposition thereof, and the resultant polymer are biocompatible. Theresultant polymer should also be biodegradable.

Finally, it is desirable that the degradation products of the resultantpolymer be both biocompatible and water soluble, so that the degradationproducts are completely eliminated from the human body as wasteproducts.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic representation of lap shear joint

FIG. 2 illustrates polymer degradation mechanisms.

SUMMARY OF THE INVENTION

The present invention relates to a monomer composition comprising atleast one alkyl ester α-cyanoacrylate monomer, that polymerizes to forman adhesive or sealant possessing exceptional adhesive/sealantcharacteristics, and is minimally toxic to non-toxic, and absorbable byliving organisms.

The α-cyanoacrylate monomers of the present invention are alkyl esterα-cyanoacrylate monomers of the general formula having a spacer R1:

wherein n is from 2 to 12; R3 and R4 is an alkyl group or a hydrogen,and at least one of R3 or R4 is an alkyl group (e.g. linear or branched,or cyclic) having from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13carbon atoms; R2 is an alkyl group (e.g. linear or branched, or cyclic)having from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13 carbon atoms;and the combined number of carbon atoms (N) in the spacer R1 is at leastn+1.

The present invention also provides a kit, comprising a saleable packagecomprising a first container that contains at least one alkyl esterα-cyanoacrylate monomer; and optionally a polymerization initiator oraccelerator in an amount effective to initiate the polymerization.

The present invention additionally provides a method of closing livingtissue, comprising applying to living tissue a monomer compositioncomprising at least one alkyl ester α-cyanoacrylate monomer andoptionally a polymerization initiator or accelerator in an amounteffective to accelerate the polymerization and to achieve satisfactorymechanical performance of the resulting polymer.

The present invention also provides a method of treating living tissue,comprising determining a desired rate at which an adhesive/sealantpolymer is absorbed; optionally selecting a suitable combination ofmonomer and polymerization initiator or accelerator to provide thedesired absorption rate; and optionally applying to living tissue thepolymerization initiator or accelerator and monomer to form anabsorbable polymer adhesive.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

For the purposes of this invention, the term “absorbable” means capableof being absorbed, degraded or biodegraded, either fully or partially,by animal (including human) tissue after application of the adhesive orsealant.

For the purposes of this invention, the term “substantially absorbed”means at least 90% absorbed.

Monomer compositions of the present invention, and polymers formedtherefrom are useful as tissue adhesives, covering for open wounds, andin other biomedical applications. More particularly, they find use in,for example, approximating tissue; apposing surgically incised ortraumatically lacerated tissues; dressing bums, skin or othersuperficial or deep tissue surface wounds (such as abrasions, chaffed orraw skin, and/or stomatitis); and aiding repair and regrowth of livingtissue.

Monomer compositions of the present invention, and polymers formedtherefrom, have broad application for sealing wounds in various livingtissue, internal organs and blood vessels; sealing wounds to retard orprevent bleeding; preventing body fluid leakage; and can be applied, forexample, on the interior or exterior of blood vessels and various organsor tissues.

The monomer composition of the present invention comprise at least onepolymerizable alkyl ester α-cyanoacrylate monomer. Specifically, theα-cyanoacrylate monomer is an alkyl ester α-cyanoacrylate monomer of thegeneral formula having a spacer R1:

n is from 2 to 12; R3 and R4 are each an alkyl group or a hydrogen, andat least one of R3 or R4 is an alkyl group (e.g. linear or branched, orcyclic) having from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13 carbonatoms; R2 is an alkyl group (e.g. linear or branched, or cyclic) havingfrom 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13 carbon atoms; and thecombined number of carbon atoms (N) in the spacer R1 is at least n+1.

It is important that the value of n is in a range such that it allowsfor feasible preparation and purification of the composition whileproviding desirable biodegradability and adhesive properties. Apreferred range for n is from about 2 to 12, a more preferred range isfrom about 2 to 8.

The combined number of carbon atoms (N) is defined as the combined valueof the number of carbon atoms on the R3 and R4 side branches and thenumber of carbon atoms on the spacer backbone (n), wherein the combinednumber of carbon atoms (N) in

is at least n+1.

A preferred combined number of carbon atoms (N) in

is 4 or greater.

A more preferred combined number of carbon atoms (N) in

is 5 or greater.

Examples of the monomers include, but are not limited to:

The alkyl ester cyanoacrylate monomers described herein can be preparedaccording to the procedure described in U.S. Pat. No. 3,995,641 toKronenthal et al., which is hereby incorporated by reference. In theKronenthal et al. method, such cyanoacrylate monomers are prepared byreacting an alkyl ester of an alpha-cyanoacrylic acid with a cyclic1,3-diene to form a Diels-Alder adduct, which is then subjected toalkaline hydrolysis followed by acidification to form the correspondingalpha-cyanoacrylic acid adduct. The alpha-cyanoacrylic acid adduct ispreferably esterified by an alkyl bromoacetate to yield thecorresponding carbalkoxymethyl alpha-cyanoacrylate adduct.Alternatively, the alpha-cyanoacrylic acid adduct may be converted tothe alpha-cyanoacrylyl halide adduct by reaction with thionyl chloride.The alpha-cyanoacrylyl halide adduct is then reacted with an alkylhydroxyacetate or a methyl substituted alkyl hydroxyacetate to yield thecorresponding carbalkoxymethyl alpha-cyanoacrylate adduct or carbalkoxyalkyl alpha-cyanoacrylate adduct, respectively. The cyclic 1,3-dieneblocking group is finally removed and the carbalkoxy methylalpha-cyanoacrylate adduct or the carbalkoxy alkyl alpha-cyanoacrylateadduct is converted into the corresponding carbalkoxy alkylalpha-cyanoacrylate by heating the adduct in the presence of a slightdeficit of maleic anhydride.

The alkyl ester α-cyanoacylate monomers can also be prepared through theKnoevenagel reaction of an alkyl cyanoacetate, or an alkyl estercyanoacetate, with paraformaldehyde. This leads to a cyanoacrylateoligomer. Subsequent thermal cracking of the oligomer results in theformation of a cyanoacrylate monomer. After further distillation, acyanoacrylate monomer with high purity (greater than 95.0%, preferablygreater than 99.0%, and more preferably greater than 99.8%) may beobtained.

Monomers prepared with low moisture content and essentially free ofimpurities (e.g., surgical grade) are preferred for biomedical use.

The alkyl ester α-cyanoacrylate monomer may be employed individually oras a comonomer with one or more alkyl ester α-cyanoacrylate monomer orother monomers such as alkyl cyanoacrylate and alkoxyalkyl cyanoacrylateincluding, but not limited to, methyl cyanoacrylate, ethylcyanoacrylate, n-butyl cyanoacrylate, isobutyl cyanoacrylate, n-octylcyanoacrylate, 2-octyl cyanoacrylate, dodecyl cyanoacrylate,2-ethylhexyl cyanoacrylate, methoxyethyl cyanoacrylate, 2-ethoxyethylcyanoacrylate, 3-methoxybutyl cyanoacrylate, 2-butoxyethylcyanoacrylate, 2-isopropoxyethyl cyanoacrylate, and 1-methoxy-2-propylcyanoacrylate.

In the event the alkyl ester α-cyanoacrylate monomers have a slowpolymerization rate, an effective agent which initiates or acceleratespolymerization of the alkyl ester cyanoacrylate monomer may be used withthe monomer composition. Initiators and accelerators particularlysuitable for use with alkyl ester α-cyanoacrylates provide a faster curerate while retaining the absorbable properties of the adhesive. Alkylester α-cyanoacrylate monomers stimulated to cure by a suitableinitiator or accelerator may be made to cure in as short as a fewseconds to a few minutes. The cure rate may be closely controlled byselection of an amount or concentration of initiator or acceleratoradded to the monomer composition and may thus be readily controlled byone skilled in the art in light of the present disclosure. A suitableinitiator provides a consistent controllable complete polymerization ofthe monomer so that the polymerization of the monomer can be made tooccur in the time desired for the particular application.

Initiators or accelerators are molecules (organic or inorganic orhybride thereof) having nucleophilic functionalities. Suchfunctionalities include but not limited to nitrogen containing groups(e.g., amino, imine, amide, imide), phosphor containing compounds (e.g.,phosphine), oxygen containing compounds (e.g., hydroxyls, carboxylate,water), sulfur containing compounds (such as thiols). Examples ofeffective inorganic initiators or accelerators include but not limitedto NaCl, NaHCO₃, Na₂CO₃ and sodium phosphates. Examples oforganic-inorganic hybride initiators or accelerators include but notlimited to metallo-organic compounds, such as Grinard agents. Suitableinitiators or accelerators are described in, for example, U.S. Pat. No.6,620,846 B1, the content is incorporated by reference herein in itsentirety.

Quaternary amine initiators or accelerators are also known to beeffective. In preferred embodiments, the present invention provides forthe use of quaternary amine polymerization initiators or acceleratorssuch as quaternary amines having the formula:

wherein R4, R5, R6 and R7 are each independently H or a substituted orunsubstituted straight, branched or cyclic alkyl group; a substituted orunsubstituted aromatic ring; a substituted or unsubstituted aralkylgroup; or a substituted or unsubstituted alkyl or aromatic group whichmay include one or more hetero atom functionalities such as oxygen,sulfur, nitrogen, etc.; and X⁻ is an anion such as a halide, for examplechloride, bromide, or fluoride, or hydroxyl. In preferred embodiments,at least one of R4, R5, R6 and R7 includes an aromatic group and/or ahetero atom functionality such as an ether or ester linkage orcorresponding linkages where the hetero atom is sulfur or nitrogen.Preferred quaternary amine initiators are selected from the groupconsisting of domiphen bromide, butyrylcholine chloride, benzalkoniumbromide and acetyl choline chloride.

Initiators may be in the form of a solid, such as a powder or a solidfilm, or in the form of a liquid, such as a viscous or paste-likematerial. The initiator or accelerator may also include a variety ofadditives, such as surfactants or emulsifiers. Preferably, the initiatoror accelerator is soluble in the monomer composition, and/or comprisesor is accompanied by at least one surfactant which, in embodiments,helps the initiator or accelerator co-elute with the monomercomposition. In embodiments, the surfactant may help disperse theinitiator or accelerator in the monomer composition.

The initiator or accelerator may be applied to tissue before the monomercomposition, or may be applied directly to the monomer composition oncethe monomer composition is applied to tissue. In embodiments, theinitiator or accelerator may be combined with the monomer compositionjust prior to applying the composition to tissue.

The selection of an initiator or accelerator may additionally affect therate at which the polymerized monomer is absorbed by living tissue.Therefore, the most suitable initiators or accelerators are those thatpolymerize the monomer at a rate suitable for medical applications whileproviding a polymer that is substantially absorbed in less than twoyears. Preferable initiators are those that absorb water as theabsorption of water encourages the degradation of the polymer. However,since not all initiators absorb water, and initiators that do absorbwater do so at different rates, the selection of an initiator based onthis property also provides for a degree of control over the degradationof the polymer. For the purposes of this invention, the phrase “suitablefor medical application(s)” means that the initiator or acceleratorpolymerizes the monomer in less than 3 minutes, preferably in less than2.5 minutes, more preferably in less than 1 minute, and often in lessthan 45 seconds.

Initiators or accelerators, such as quaternary amines mentioned above,are preferably used in the present invention, but other initiators oraccelerators may also be selected by one of ordinary skill in the artwithout undue experimentation. Such suitable initiators or acceleratorsmay include, but are not limited to, detergent compositions;surfactants: e.g., nonionic surfactants such as polysorbate 20 (e.g.,Tween 20® from ICI Americas), polysorbate 80 (e.g., Tween 80® from ICIAmericas) and poloxamers, cationic surfactants such astetrabutylammonium bromide, anionic surfactants such as sodiumtetradecyl sulfate, and amphoteric or zwitterionic surfactants such asdodecyldimethyl(3-sulfopropyl)ammonium hydroxide, inner salt; amines,imines and amides, such as imidazole, tryptamine, urea, arginine andpovidine; phosphines, phosphites and phosphonium salts, such astriphenylphosphine and triethyl phosphite; alcohols such as ethyleneglycol, methyl gallate, ascorbic acid, tannins and tannic acid;inorganic bases and salts, such as sodium bisulfite, magnesiumhydroxide, calcium sulfate and sodium silicate; sulfur compounds such asthiourea and polysulfides; polymeric cyclic ethers such as monensin,nonactin, crown ethers, calixarenes and polymeric epoxides; cyclic andacyclic carbonates, such as diethyl carbonate; phase transfer catalystssuch as Aliquat 336; organometallics such as cobalt naphthenate andmanganese acetylacetonate; and radical initiators or accelerators andradicals, such as di-t-butyl peroxide and azobisisobutyronitrile.

Specific compositions of the invention may have various combinations ofalkyl ester α-cyanoacrylate monomers and thickeners, plasticizers,colorants, preservatives, heat dissipating agents, stabilizing agentsand the like, which will be described in more detail below. Preferably,a composition of this invention has from 65 to 99.9 weight % of an alkylester α-cyanoacrylate monomer and is promoted to polymerize by 0.005 to10 weight % of an initiator or accelerator. More preferably, acomposition of this invention has from 80 to 99.9 weight % of an alkylester α-cyanoacrylate monomer and is promoted to polymerize by 0.02 to10 weight % of an initiator or accelerator. Even more preferably, acomposition of this invention has 85 to 99.9 weight % of an alkyl esterα-cyanoacrylate monomer, such as 3-(2-Cyano-acryloyloxy)-butyric acidethyl ester and 3-(2-Cyano-acryloyloxy)-hexanoic acid ethyl ester, andis promoted to polymerize by 0.05 to 5 weight % of an initiator oraccelerator, such as domiphen bromide. Compositions of this inventionmay also include 0 to 25, more preferably 0 to 10, for example 0 to 5weight % based on a total weight of the composition of at least one ofthe following: thickeners, plasticizers, colorants, preservatives, heatdissipating agents, stabilizing agents and the like. Of course, othercompositions based on other proportions and/or components can readily beprepared according to embodiments of the present invention in light ofthe present disclosure.

The composition may also optionally include preservatives. Apreservative may be selected from among preservatives including, but notlimited to, parabens and cresols. For example, suitable parabensinclude, but are not limited to, alkyl parabens and salts thereof, suchas methylparaben, methylparaben sodium, ethylparaben, propylparaben,propylparaben sodium, butylparaben, and the like. Suitable cresolsinclude, but are not limited to, cresol, chlorocresol, and the like. Thepreservative may also be selected from other known agents including, butnot limited to, hydroquinone, pyrocatechol, resorcinol, 4-n-hexylresorcinol, captan (i.e.,3a,4,7,7a-tetrahydro-2-((trichloromethyl)thio)-1H-isoindole-1,3(2H)-dione),benzoic acid, benzyl alcohol, chlorobutanol, dehydroacetic acid,o-phenylphenol, phenol, phenylethyl alcohol, potassium benzoate,potassium sorbate, sodium benzoate, sodium dehydroacetate, sodiumpropionate, sorbic acid, thimerosal, thymol, phenylmercuric compoundssuch as phenylmercuric borate, phenylmercuric nitrate and phenylmercuricacetate, formaldehyde, and formaldehyde generators such as thepreservatives Germall II® and Germall 115® (imidazolidinyl urea,available from Sutton Laboratories, Charthan, N.J.). Other suitablepreservatives are disclosed in U.S. patent application Ser. No.09/430,180, filed Oct. 29, 1999, the entire disclosure of which ishereby incorporated by reference. In embodiments, mixtures of two ormore preservatives may also be used.

Monomer compositions of the invention may also include a heatdissipating agent. Heat dissipating agents include liquids or solidsthat may be soluble or insoluble in the monomer. The liquids may bevolatile and may evaporate during polymerization, thereby releasing heatfrom the composition. Suitable heat dissipating agents may be found inU.S. Pat. No. 6,010,714 to Leung et al., the entire disclosure of whichis incorporated herein.

The composition may also optionally include at least one plasticizingagent that imparts flexibility to the polymer formed from the monomer.The plasticizing agent preferably contains little or no moisture andshould not significantly affect the stability or polymerization of themonomer. Such plasticizers are useful in polymerized compositions to beused for closure or covering of wounds, incisions, abrasions, sores orother applications where flexibility of the adhesive is desirable. Somethickeners, such as poly-2-ethylhexylcyanoacrylate, may also impartflexibility to the polymer.

Examples of suitable plasticizers include acetyl tributyl citrate,dimethyl sebacate, triethyl phosphate, tri(2-ethylhexyl)phosphate,tri(p-cresyl) phosphate, glyceryl triacetate, glyceryl tributyrate,diethyl sebacate, dioctyl adipate, isopropyl myristate, butyl stearate,lauric acid, trioctyl trimellitate, dioctyl glutarate,polydimethylsiloxane, and mixtures thereof. Preferred plasticizers aretributyl citrate and acetyl tributyl citrate. In embodiments, suitableplasticizers include polymeric plasticizers, such as polyethylene glycol(PEG) esters and capped PEG esters or ethers, polyester glutarates andpolyester adipates.

The addition of plasticizing agents in amounts ranging from about 0.1wt. % to about 25 wt. % provides increased elongation and toughness ofthe polymerized monomer over polymerized monomers not havingplasticizing agents. The composition may also include at least onethickening agent. Suitable thickening agents include, for example,polycyanoacrylates, polylactic acid, polyglycolic acid, lactic-glycolicacid copolymers, polycaprolactone, lactic acid-caprolactone copolymers,poly-3-hydroxybutyric acid, polyorthoesters, polyalkyl acrylates,copolymers of alkylacrylate and vinyl acetate, polyalkyl methacrylates,and copolymers of alkyl methacrylates and butadiene.

The composition may also optionally include at least one thixotropicagent. Suitable thixotropic agents are known to the skilled artisan andinclude, but are not limited to, silica gels such as those treated witha silyl isocyanate. Examples of suitable thixotropic agents aredisclosed in, for example, U.S. Pat. No. 4,720,513, the disclosure ofwhich is hereby incorporated in its entirety.

The composition may also optionally include at least one natural orsynthetic rubber to impart impact resistance, which is preferableespecially for industrial compositions of the present invention.Suitable rubbers are known to the skilled artisan. Such rubbers include,but are not limited to, dienes, styrenes, acrylonitriles, and mixturesthereof. Examples of suitable rubbers are disclosed in, for example,U.S. Pat. Nos. 4,313,865 and 4,560,723, the disclosures of which arehereby incorporated in their entireties.

The composition may also optionally include at least one anionic vaporphase stabilizer and/or at least one anionic liquid phase stabilizer.These stabilizing agents inhibit premature polymerization. Suchstabilizing agents may also include mixtures of anionic stabilizingagents and radical stabilizing agents. Any mixture of stabilizers isincluded as long as the mixture does not adversely affect the desiredpolymerization and absorption of the monomer. Suitable stabilizingagents are disclosed in, for example, U.S. Pat. No. 6,512,023, theentire disclosure of which is hereby incorporated by reference.

Compositions of the present invention are believed to reduce toxicitycompared to other cyanoacrylates, such as methyl cyanoacrylate and ethylcyanoacrylate, due to the absorbable nature of the side-chain structuralmoieties in the alkyl ester α-cyanoacrylates, such as3-(2-Cyano-acryloyloxy)-butyric acid ethyl ester (Et-β-HBT-CA) and3-(2-Cyano-acryloyloxy)-hexanoic acid ethyl ester (Et-β-CPL-CA).However, medical compositions of the present invention may also includeat least one biocompatible agent effective to reduce active formaldehydeconcentration levels produced during in vivo biodegradation of thepolymer (also referred to herein as “formaldehyde concentration reducingagents”). Preferably, this component is a formaldehyde scavengercompound. Examples of formaldehyde scavenger compounds useful in thisinvention include sulfites; bisulfites; mixtures of sulfites andbisulfites; ammonium sulfite salts; amines; amides; imides; nitriles;carbamates; alcohols; mercaptans; proteins; mixtures of amines, amides,and proteins; active methylene compounds such as cyclic ketones andcompounds having a β-dicarbonyl group; and heterocyclic ring compoundsfree of a carbonyl group and containing an NH group, with the ring madeup of nitrogen or carbon atoms, the ring being unsaturated or, whenfused to a phenyl group, being unsaturated or saturated, and the NHgroup being bonded to a carbon or a nitrogen atom, which atom isdirectly bonded by a double bond to another carbon or nitrogen atom.

Other examples of formaldehyde level reducing compounds and compositionsare exemplified by U.S. Pat. Nos. 6,010,714; 5,624,669; 5,582,834;5,575,997, the entire disclosures of which are hereby incorporated byreference.

To improve the cohesive strength of adhesives formed from thecompositions of this invention, difunctional monomeric cross-linkingagents may be added to the monomer compositions of this invention. Suchcrosslinking agents are known. U.S. Pat. No. 3,940,362 to Overhults,which is hereby incorporated in its entirety by reference, disclosessuch cross-linking agents. Examples of suitable crosslinking agentsinclude alkyl bis(2-cyanoacrylates), triallyl isocyanurates, alkylenediacrylates, alkylene dimethacrylates, trimethylol propane triacrylate,and alkyl bis(2-cyanoacrylates). In accordance with the presentdisclosure, a catalytic amount of an amine activated free radicalinitiator, accelerator or rate modifier may be added to initiatepolymerization or to modify the rate of polymerization of thecyanoacrylate monomer/crosslinking agent blend.

To improve the adhesion between substrates (e.g. tissue surface) and thecompositions of this invention, priming agents may be used to conditionthe substrate prior to applying in the alkyl ester α-cyanoacrylates.Suitable primers include, but not limited to, ph-modifying agents (e.g.organic or inorganic bases), ionic and non-ionic surfactants, andorganic or inorganic salts. Other suitable priming agents can be readilyidentified by one skilled in the art in light of the present disclosure.

The compositions of this invention may further contain fibrousreinforcement and colorants such as dyes, pigments, and pigment dyes.Examples of suitable fibrous reinforcement include PGA microfibrils,collagen microfibrils, cellulosic microfibrils, and olefinicmicrofibrils. Examples of suitable colorants include1-hydroxy-4-[4-methylphenyl-amino]-9,10 anthracenedione (D+C violet No.2); disodium salt of6-hydroxy-5-[(4-sulfophenyl)axo]-2-naphthalene-sulfonic acid (FD+CYellow No. 6);9-(o-carboxyphen0yl)-6-hydroxy-2,4,5,7-tetraiodo-3H-xanthen-3-one,disodium salt, monohydrate (FD+C Red No. 3);2-(1,3-dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene)-2,3-dihydro-3-oxo-1H-indole-5-sulfonicacid disodium salt (FD+C Blue No. 2); and [phthalocyaninato (2-)]copper. Other modifications to compositions of the present invention areexemplified by U.S. Pat. Nos. 5,624,669; 5,582,834; 5,575,997;5,514,371; 5,514,372; and 5,259,835; and U.S. patent application Ser.No. 08/714,288, the disclosures of all of which are hereby incorporatedin their entirety by reference.

In embodiments of the present invention, the composition may alsooptionally include at least one biological or therapeutical agent. Thevariety of biological/therapeutical agents that can be used inconjunction with the plurality of packed particles of the invention isvast. In general, biological/therapeutical agents which may beadministered adhesive/sealant compositions of the invention include,without limitation, antiinfectives, such as antibiotics, antimicrobialagents (e.g. Diiodomethyl-p-tolylsulfone,2,4,4′-Trichloro-2′-Hydroxydiphenyl Ether or combination thereof ) andantiviral agents; analgesics and analgesic combinations; anorexics;antihelmintics; antiarthritics; antiasthmatic agents; anticonvulsants;antidepressants; antidiuretic agents; antidiarrheals; antihistamines;antiinflammatory agents; antimigraine preparations; antinauseants;antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics;antipyretics, antispasmodics; anticholinergics; sympathomimetics;xanthine derivatives; cardiovascular preparations including calciumchannel blockers and beta-blockers such as pindolol and antiarrhythmics;antihypertensives; diuretics; vasodilators, including general coronary,peripheral and cerebral; central nervous system stimulants; cough andcold preparations, including decongestants; hormones, such as estradioland other steroids, including corticosteroids; hypnotics;immunosuppressives; muscle relaxants; parasympatholytics;psychostimulants; sedatives; tranquilizers; naturally derived orgenetically engineered proteins, polysaccharides, glycoproteins, orlipoproteins; oligonucleotides, antibodies, antigens, cholinergics,chemotherapeutics, radioactive agents, osteoinductive agents,cystostatics heparin neutralizers, procoagulants and hemostatic agents,such as prothrombin, thrombin, fibrinogen, fibrin, fibronectin,heparinase, Factor X/Xa, Factor VII/VIIa, Factor IX/IXa, Factor XI/XIa,Factor XII/XIIa, tissue factor, batroxobin, ancrod, ecarin, vonWillebrand Factor, collagen, elastin, albumin, gelatin, platelet surfaceglycoproteins, vasopressin, vasopressin analogs, epinephrine, selectin,procoagulant venom, plasminogen activator inhibitor, platelet activatingagents and synthetic peptides having hemostatic activity.

Compositions of the present invention may be utilized in conjunctionwith other sealing means. For example, an adhesive may be applied to awound that has been closed using surgical suture, tape, or staples.Adhesives of the present invention may also be used in conjunction withother sealing means, such as means identified in U.S. Pat. No.6,014,714, the entire disclosure of which is incorporated herein byreference.

Compositions of the present invention may be applied in single ormultiple applications. The adhesives may be applied in a first layer,and after the first layer is allowed to fully or partially polymerize, asubsequent layer may be added. Such a process may be conducted numeroustimes, depending on the size of the wound and the amount of adhesiveapplied in each application.

The monomer composition may be packaged in any type of suitablecontainer fabricated from materials including, but not limited to,glass, plastic, metal packages, and film-formed packages. Suitablecontainers preferably include those into which the compositions may bedispensed and sterilized without unacceptable damage to, or degradationof, the container or the components of the monomer composition.Post-halogenated (e.g., fluourinated) or silanized polymeric barrierlayers on at least the monomer-contacting surfaces of the containerprovide a superior shelf-life for monomer compositions, as disclosed inU.S. patent application Ser. No. 09/430,289, filed Oct. 29, 1999, theentire disclosure of which is hereby incorporated by reference. Glass isespecially preferred when sterilization is achieved with dry heatbecause of the lack of stability of many plastics at temperatures usedfor dry heat sterilization (typically at least about 140° C.). Examplesof types of containers include, but are not limited to, ampoules, vials,syringes, pipettes, and the like.

The present invention also provides a saleable kit for delivering anabsorbable cyanoacrylate adhesive to tissue. The kit comprises asaleable package comprising a first container that contains at least onealkyl ester α-cyanoacrylate monomer; and a polymerization initiator oraccelerator.

The kit may comprise a second container containing the initiator oraccelerator. Or, the first container could have the initiator oraccelerator in or on it as long as the initiator or accelerator is notin contact with the monomer prior to the desired use. The initiator oraccelerator is selected so that it functions in conjunction with theco-packaged polymerizable monomer composition to initiate polymerizationof the monomer or modify (e.g., accelerate) the rate of polymerizationfor the monomer to form a polymeric adhesive. The proper combination ofinitiator or accelerator and polymerizable monomer can be determined byone of skill in the art without undue experimentation in light of thepresent disclosure. The kit may also include a brush, swab or sponge toassist in applying the composition to living tissue. The kit is alsopreferably sterilized; however, the containers and components may besterilized separately or together. Preferably, kits and the kitcomponents (including compositions) of the present invention have asterility level in the range of 10⁻³ to 10⁻⁶ Sterility Assurance Level(SAL) and are sterile for surgical purposes. Various designs of suchkits are disclosed, for example, in U.S. patent application Ser. No.09/385,030, filed Aug. 30, 1999, the entire disclosure of which isherein incorporated by reference. The sterilization may be accomplishedby techniques known to the skilled artisan, and is preferablyaccomplished by methods including, but not limited to, chemical,physical, and irradiation methods. Examples of physical methods include,but are not limited to, sterile fill, filtration, sterilization by heat(dry or moist) and retort canning. Examples of irradiation methodsinclude, but are not limited to, gamma irradiation, electron beamirradiation, and microwave irradiation.

In embodiments of the present invention, any suitable applicator may beused to apply the adhesive composition to a substrate. For example, theapplicator may include an applicator body, which is formed generally inthe shape of a tube having a closed end, an open end, and a hollowinterior lumen, which holds a crushable or frangible ampoule. Theapplicator and its related packaging may be designed as a single-useapplicator or as a multi-use applicator. Suitable multi-use applicatorsare disclosed, for example, in U.S. patent application Ser. No.09/385,030, filed Aug. 30, 1999, the entire disclosure of which isincorporated herein by reference.

In embodiments of the invention, the applicator may comprise elementsother than an applicator body and an ampoule. For example, an applicatortip may be provided on the open end of the applicator. The applicatortip material may be porous, absorbent, or adsorbent in nature to enhanceand facilitate application of the composition within the ampoule.Suitable designs for applicators and applicator tips that may be usedaccording to the present invention are disclosed in, for example, U.S.Pat. No. 5,928,611 to Leung and U.S. patent applications Ser. Nos.09/069,979, filed Apr. 30, 1998, 09/069,875, filed Apr. 30, 1998,09/479,059, filed Jan. 7, 2000, and 09/479,060, filed Jan. 7, 2000, theentire disclosures of which are incorporated herein by reference.

In embodiments of the present invention, an applicator may contain theinitiator or accelerator on a surface portion of the applicator orapplicator tip, or on the entire surface of the applicator tip,including the interior and the exterior of the tip. When the initiatoror accelerator is contained in or on an applicator tip, the initiator oraccelerator may be applied to the surface of the applicator tip or maybe impregnated or incorporated into the matrix or internal portions ofthe applicator tip. Additionally, the initiator or accelerator may beincorporated into the applicator tip, for example, during thefabrication of the tip.

In other embodiments, the initiator or accelerator may be coated on aninterior surface of the applicator body and/or on an exterior surface ofan ampoule or other container disposed within the applicator body, maybe placed in the applicator body in the form of a second frangible vialor ampoule and/or may be otherwise contained within the applicator body,so long as a non-contacting relationship between the polymerizablemonomer composition and the initiator or accelerator is maintained untiluse of the adhesive.

Various designs of applicators and methods for incorporating theinitiator or accelerator into the applicator are disclosed in U.S. Pat.No. 5,928,611 to Leung and U.S. patent applications Ser. Nos.09/069,979, filed Apr. 30, 1998, 09/069,875, filed Apr. 30, 1998,09/145,200, filed Sep. 1, 1998, the entire disclosures of which areincorporated herein by reference.

Alkyl ester α-cyanoacrylate monomers are particularly useful for medicalapplications because of the absorbability thereof and of the resultantpolymer by living tissue and associated fluids. According to the presentinvention, the polymerized and applied cyanoacrylate monomer issubstantially absorbed in a period of less than 2 years, preferablyapproximately 2-24 months, more preferably 3-18 months, and mostpreferably 6-12 months after application to living tissue.

The absorption rate of the polymerized monomer is affected by severalfactors including the character of the composition and the quantity ofthe composition applied. For example, regulating the pH of an immediatein vivo environment of the composition may aid in regulating polymerdegradation, as disclosed in U.S. patent application Ser. No.08/714,288, filed Sep. 18, 1996, the entire disclosure of which ishereby incorporated by reference.

The selection of monomer may affect the absorption rate of the resultantpolymer, as well as the polymerization rate of the monomer. For example,without being bound by theory, it is believed that the more hygroscopicthe initiator, the more rapid will be the degradation of the polymer.Two or more different monomers that have varied absorption and/orpolymerization rates may be used in combination to give a greater degreeof control over the absorption rate of the resultant polymer, as well asthe polymerization rate of the monomer. Thus, an important aspect ofembodiments of the invention lies in the selection of the monomer andinitiator to control within relatively narrow and predictable rangesboth the polymerization and absorption rates.

The compositions described herein have multiple medical applications.For example, as an internal surgical adhesive and sealant, the adhesivecan bond tissue to tissue, tissue to medical device (e.g. meshes, clipsand films) and medical device to medical device. As a sealant, thecomposition can be coated on a tissue, or on a medical device, or on theinterface of a medical device with tissue to prevent leaks. Thecomposition can be used to form films in situ that may have applicationssuch as for the prevention of surgical adhesions. The composition can beused to form foams in situ that may have applications such as a filler(e.g. dead space removal, reconstructive and cosmetic surgeries),bulking agents, tissue engineering (e.g. scaffolds) materials and otherswhere foams and sponges are useful. The composition can be formulated sothat it is injectable and used to form gels in situ that are localized,and adherent to tissue, staying at the site where they are injected.These may have applications such as a delivery matrix for cells andother biologicals, bioactive agents and pharmaceutical or neutraceuticalagents, and as embolization agents, and as means to localize contrastingagents.

As a surgical sealant/adhesive, it can be used as an adjunct to primarywound closure devices, such as staples, sutures, meshes to sealpotential leaks of gasses, liquids, or solids. More specifically, thesurgical adhesive/sealant may be applied to a tissue as a part of asurgical procedure, in various forms, for example: liquid, powder, film,sponge or foam, impregnated fabric, impregnated sponge or foam, orspray.

As a filler, the monomer composition may be used as a facial, defect orvoid filler. For example, the composition may be applied in theinterstices of an internal void and allowed to polymerize therein, suchthat the resultant polymer fills the internal cavities and voids,penetrating and conforming to the interstices and pores of the tissue.The composition may be used after a broad number of procedures havingpotential risk of dead space formation, including, but not limited to,radical mastectomy (i.e. breast and regional lymph nodes removal forcancer treatment), breast reconstruction and augmentation procedure,reconstructive or cosmetic abdominoplasty and liposuction, face-lift,cesarean section and hysterectomy in obese patients, orthopedicprocedures on thigh region, incisional hernia repair, lipoma excision,and traumatic lesions, i.e. closed trauma.

EXAMPLES

The present invention will be further understood by reference to thefollowing non-limiting examples.

Example 1A Synthesis of 3-(2-Cyano-acetoxy)-butyric acid ethyl ester(Et-β-HBT-CAc)

A mixture of 194.0 g of ethyl-3-hydroxybutyrate, 149.83 g of cyanoaceticacid, and 10.76 g of 4-dimethylaminopyridine (DMAP) was stirred in 1500ml of CH₂Cl₂ in a 3 L three-neck round bottom flask equipped with amechanical stirrer. About 75 ml of N-N′-dimethylformamide (DMF) wasadded to the above mixture to make a clear solution. The above solutionwas chilled in an ice water bath. A separately prepareddicyclohexylcarbodiimide (DCC) solution (363.45 g in 600 ml CH₂Cl₂) wasadded to the above chilled solution by using an addition funnel. Whiteprecipitate formed within five minutes after the start of the addition.The reaction mixture was left stirred overnight.

The precipitate was first removed by filtration and the filtrate wasevaporated by rotary evaporation to remove solvent. The desired product(3-(2-Cyano-acetoxy)-butyric acid ethyl ester) was obtained bydistillation under vacuum twice. A total of 212.5 g (73% yield) ofcolorless liquid was collected.

¹H NMR (CDCl₃, δ ppm): 5.39(m, 1H), 4.16(q, 2H), 3.42(s, 2H), 2.62(m,2H), 1.37(d, 3H), 1.27(t, 3H) GC-MS: 99.4%.

Boiling point: 100˜109° C./0.20˜0.27 mmHg.

Example 1B Synthesis of 3-(2-Cyano-acryloyloxy)-butyric acid ethyl ester(Et-β-HBT-CA)

A mixture of 39.84 g of 3-(2-Cyano-acetoxy)-butyric acid ethyl ester(Et-β-HBT-CAc), 6.6 g of paraformaldehyde, 0.06 ml of piperidine and 150ml benzene was stirred in a 250 ml round bottomed flask equipped with amagnetic stir bar. A Dean-Stark trap and a condenser were attached tothe reaction flask. The reaction flask was immersed in an oil bath. Thereaction mixture was heated to reflux and the reaction was allowedovernight.

The slightly brown colored reaction mixture was evaporated using arotary evaporator to remove the solvent, yielding a brown coloredviscous residue which turned into a solid gel after cooling to roomtemperature. This solid gel was oligomer of3-(2-Cyano-acryloyloxy)-butyric acid ethyl ester.

To the above oligomer, 0.20 g of hydroquinone (HQ) and 2.0 g of P₂O₅were added. A simple vacuum distillation was set up where all glasswarepieces were previously treated with 5N H₂SO₄ solution and dried in avacuum oven after rinsing by deionized water (DI water). The abovemixture of oligomer, hydroquinone and P₂O₅ was heated to up to 140° C.to remove low boiling impurities then to above 160° C. in an oil bathunder vacuum to carry out the depolymerization. The crude monomerobtained was distilled one more time under vacuum. A total of 8.4 g (20%yield) of colorless liquid was obtained as the final monomer product(3-(2-Cyano-acryloyloxy)-butyric acid ethyl ester).

A very small amount of this monomer product was placed in between twomoist fingertips and bonded the fingertips strongly within one minute.

¹H NMR (CDCl₃, δ ppm): 7.03(s, 1H), 6.60(s, 1H), 5.43(m, 1H), 4.15(q,2H) 2.65(m, 2H), 1.40(d, 3H), 1.23(t, 3H) GC-MS: 98.3%.

Boiling point: 114˜115° C./0.17 mmHg

Example 2A Synthesis of 3-(2-Cyano-acetoxy)-hexanoic acid ethyl ester(Et-β-CPL-CAc)

A mixture of 100.14 g of ethyl-3-hydroxyhexanoate, 63.75 g ofcyanoacetic acid, and 4.58 g of 4-dimethylaminopyridine (DMAP) in 625 mlof CH₂Cl₂ was stirred in a 2 L three-neck round bottom flask equippedwith a mechanical stirrer. About 31 ml of N-N′-dimethylformide (DMF) wasadded to make a clear solution. The above clear solution was chilled inan ice water bath. A separately prepared dicyclohexylcarbodiimide (DCC)solution (154.75 g in 250 ml CH₂Cl₂) was added to the above chilledsolution by using an addition funnel. White precipitate formed withinfive minutes after the start of the addition. The reaction mixture wasleft stirred overnight.

The precipitate was first removed by filtration and the filtrate wasevaporated by rotary evaporation to remove the solvent. The desiredproduct was obtained by distillation under vacuum twice. A total of 86.0g (61% yield) of colorless liquid was collected.

¹H NMR (CDCl₃, δ ppm): 5.35(m, 1H), 4.15(q, 2H), 3.42(s, 2H), 2.62(m,2H) 1.63(m, 2H), 1.37(m, 2H), 1.24(t, 3H), 0.95(t, 3H) GC-MS: 99.4%.

Boiling point: 115˜130° C./˜0.43 mmHg.

Example 2B Synthesis of 3-(2-Cyano-acryloyloxy)-hexanoic acid ethylester (Et-β-CPL-CA)

Following the same procedures and utilizing the same apparatus asdescribed in example 1B, instead, 45.45 g of3-(2-Cyano-acetoxy)-hexanoic acid ethyl ester (Et-β-CPL-CAc), 6.6 g ofparaformaldehyde, 0.06 ml of piperidine, 0.20 g of HQ, 2.0 g of P₂O₅ and150 ml benzene were used.

As described in example 1B, the crude product was further purified bysecond distillation under vacuum. A total of 9.6 g (20% yield) of finalproduct was obtained as colorless liquid.

A very small amount of this product was placed in between two moistfingertips and bonded the fingertips strongly within one minute.

¹H NMR (CDCl₃, δ ppm): 7.03(s, 1H), 6.60(s, 1 H), 5.40(m, 1 H), 4.15(q,2H), 2.65(m, 2H), 1.70(m, 2H), 1.38(m, 2H), 1.22(t, 3H), 0.95(t, 3H)GC-MS: 99.0%

Boiling point: 107˜114° C./˜0.40 mmHg.

Example 3A

Synthesis of cyano-acetic acid 1-butoxycarbonyl-ethyl ester (Bu-Lac-CAc)

A mixture of 292.32 g of butyllactate, 204.14 g of cyanoacetic acid, and14.66 g of 4-dimethylaminopyridine (DMAP) in 2000 ml of CH₂Cl₂ wasstirred in a 3 L three-neck round bottom flask equipped with amechanical stirrer. About 50 ml of N-N′-dimethylformide (DMF) was addedto make a clear solution. The above clear solution was chilled in an icewater bath. A separately prepared dicyclohexylcarbodiimide (DCC)solution (495.19 g in 500 ml CH₂Cl₂) was added to the above chilledsolution by using an addition funnel. White precipitate formed withinfive minutes after the start of the addition. The reaction mixture wasleft stirred overnight.

The precipitate was first removed by filtration and the filtrate wasevaporated by rotary evaporation to remove the solvent. The desiredproduct was obtained by distillation under vacuum twice. A total of266.0 g (62% yield) of colorless liquid was collected.

¹H NMR (CDCl₃, δ ppm): 5.17(q, 1H), 4.19(t, 2H), 3.57(s, 2H), 1.62(m,2H), 1.56(d, 3H), 1.39(m, 2H), 0.95(t, 3H), GC-MS: 97.0%

Boiling point: 87˜97° C./0.10˜0.19 mmHg.

Example 3B Synthesis of 2-Cyano-acrylic acid 1-butoxycarbonyl-ethylester (Bu-Lac-CA)

Following the same procedures and utilizing the same apparatus asdescribed in example 1B, instead, 85.29 g of cyano-acetic acid1-butoxycarbonyl-ethyl ester (Bu-Lac-CAc), 13.2 g of paraformaldehyde,0.12 ml of piperidine, 0.40 g of HQ, 4.0 g of P₂O₅ and 250 ml benzenewere used.

As described in example 1B, the crude product was further purified bysecond distillation under vacuum. A total of 38.2 g (42% yield) of finalproduct was obtained as colorless liquid.

A very small amount of this product was placed in between two moistfingertips and bonded the fingertips strongly within one minute.

¹H NMR (CDCl₃, δ ppm): 7.12(s, 1H), 6.68(s, 1H), 5.21(q, 1H), 4.19(t,2H), 1.62(m, 5H), 1.38(m, 2H), 0.96(t, 3H). GC-MS: 99.2%

Boiling point: 89˜99° C./0.31˜0.41 mmHg.

Example 4

General Procedure for Lap Shear Testing Using Pig Skin

Fresh pig skin was harvested from the back of the pig within 5 hourspost sacrifice. The hair was removed by trimming and shaving to expose asmooth skin surface. The fat attached to the inside skin surface wastrimmed away. The skin was cut into 2″×1″ coupons and covered by salinemoist paper towel before use.

The external surface of the skin was used as bonding surface to preparethe lap shear joint samples.

The coupons were patted dry prior to forming the lap shear joint. About100 μl of adhesive was deposited to one coupon within ½″ from the nearerend and smoothed to cover a ½″×1″ area (FIG. 1). The other coupon wasplaced over the area of the coupon with applied adhesive to form anoverlap of ½″×1″. A 1 lb weight was placed on top of the overlap area.The joint was allowed to cure for 20˜30 min and the strength of thejoint was tested as described below.

The strength of the cured joint was tested using an Instron (Model 5544)with a pulling rate of 5 mm/min. The maximum load for the joint to failwas recorded.

Typically, about 10 joint samples were tested for each adhesive. Resultsare summarized in Table 1.

TABLE 1 Lap shear data (Invention) (Invention) (Comparative)(Comparative) (Comparative) Monomer Et-β-HBT-CA Et-β-CPL-CA Bu-Lac-CAEt-ε-CPL-CA Et-α-CPL-CA Load (Ib) 4.09 ± 0.48 4.49 ± 0.68 4.96 ± 0.673.68 ± 0.64 1.26 ± 0.29

As shown in Table 1, both the spacer length (n) and the chain lengths ofR3 and R4 of the monomer have impacts on the physical performance of thecorresponding polymers formed thereof.

Example 5

General Procedure for in vitro Degradation Studies

A 1″×1″ Prolene™ mesh (Ethicon, Inc.) was briefly rinsed with 0.5% wtNaHCO₃ aqueous solution and patted dry. The mesh was placed on a freshlyprepared Agar plate in a petri dish and about 100 mg of monomer adhesivewas applied and spread evenly across the mesh. The monomer adhesive wasallowed to cure completely overnight with the petri dish covered andsealed with parafilm. The fully cured polymer film formed over the meshwas removed and rinsed with deionized water to remove any Agar attachedand patted dry with paper towel. The thickness of the polymer film wasabout 0.6 mm.

The above film was placed in a hydrolysis chamber with 100 ml deionizedwater while the temperature of the solution was maintained at 75° C. ThepH of the solution was maintained at 7.27 with addition of 0.05N NaOHaqueous solution during the degradation of the polymer film. The amountof the NaOH solution required to maintain pH of 7.27 was recorded as afunction of time. The degradation time was defined as the time requiredfor the medium to consume 90% of the total consumed NaOH solution. Thedegradation time of each polymer was summarized in Table 2.

In addition, the glass transition temperatures (Tg) of the abovepolymers were also reported in Table 2.

TABLE 2 In vitro degradation and polymer film properties (Invention)(Invention) (Comparative) Adhesive Polymers Et-β-HBT-CA Et-β-CPL-CABu-Lac-CA Degradation time (h) 54.6 39.4 49.4 Glass Transition 32 −11 52Temperature (Tg, ° C.)

As shown in Table 2, the polymers formed from the compositions of thepresent invention demonstrated Tg lower than body temperature (i.e. 37°C.) which is favorable particularly for medical applications, therefore,it may not be necessary to use plasticizers for the monomer adhesiveformulation.

Two mechanisms have been proposed for the degradation of cyanoacrylatepolymers via reverse Knoevenagel reaction (F. Leaonard et al., J. Appl.Polym., 10, 259-272, 1966) and side-chain hydrolysis (V. Lenaerts, etal., Biomaterials, 5, 65-68, 1984). The degradation of the titlecyanoacrylate polymers may happen through both mechanisms concurrentlyas illustrated in FIG. 2. There are two possible degradation points viathe side-chain mechanism as indicated.

The presence of the hydrolysable side-chain ester functionality isbelieved to be favorable for the side-chain hydrolysis mechanism thatmay reduce the generation of formaldehyde as a degradation product,which results from the reverse Knoevenagel reaction mechanism. Theside-chain hydrolysis degradation products are believed to include theside-chain ester structure or its fragments such as alcohols and acids,which may not be of great safety concern.

1. A method of treating living tissue, comprising: applying to livingtissue a monomer composition comprising at least one alkyl esterα-cyanoacrylate monomer of the formula:

having a spacer R1,

wherein n is from 2 to 12; R3 and R4 are each an alkyl group or ahydrogen, and at least one of R3 or R4 is an alkyl group having fromabout 1 to 13 carbon atoms; R2 is an alkyl group having from about 1 to13 carbon atoms; and the combined number of carbon atoms (N) in thespacer R1 is at least n+1.